Abstract: The major functions of the gut epithelial compartment in a complex organism is to provide a protective barrier from pathogenic organisms that gain entry through the GI tract as well as facilitate the absorption and distribution of needed nutrients. These functions are accomplished by the concerted action of a number of diverse yet interacting cell types including epithelial cells, stromal elements and cells of the immune system. The varied cell types are structurally organized and function to produce a working tissue system that can provide these major functions and contribute to host survival. Our central hypothesis is that dysfunction of any of these cell types will have adverse effects on the capacity of the tissue to carry out these functions. In particular, we reason that cells of the immune system are an essential component for the functioning of the gut epithelia and they not only play a role in the initial host response to enteric pathogens but also are likely to function, through the release of soluble mediators and/or cell-cell interactions, in the maintenance of the integrity and function of the epithelium. In this set of studies we will seek to understand how a novel subset of intraepithelial lymphocytes, ?/d T cells, contribute to the functioning of the gut epithelial barrier. Three specific aims are proposed: 1. Using an expression based approach determine if specific genes and/or pathways are altered in the small intestine of mice deficient in ?/d T cells. 2. Based on the information obtained in Aim 1, address how these alterations can impact on the structure or function of the mucosal epithelium. 3. Determine if the lack of ?/d T cells will have an impact on components of the host response to enteric infection. The described studies will provide basic insights into the complex interrelationship between immune and non-immune cells types that impact on the mucosal compartment and identify those pathways that are affected by an altered mucosal immune compartment. In addition these studies will increase our understanding of the immunobiology of ?/d T cells localized to the gut. Furthermore, these studies will likely identify specific molecular targets for rational therapeutic intervention of disease states that lead to either an increased susceptibility to enteric infection or mediate immune-mediated tissue damage. There is considerable interest in how the various cell types that compose the mucosal compartment interact so as to ensure the survival of the host. These functions include acting as a barrier form environmental challenges (infections, toxins, etc.), allowing for the transport of essential nutrients and serving as the site of first encounter with enteric pathogens. The studies described in this application utilize a mouse system to gain basic insights into how a novel resident immune cell type, the TCR ?/d T cell, contributes to the overall function of the intestinal epithelial barrier. These studies will likely identify specific molecular targets for rational therapeutic intervention of disease states that lead to either an increased susceptibility to enteric infection or mediate immune-mediated tissue damage